Topical Application of Apremilast in the Treatment of Mild to Moderate Psoriasis

Research Article | DOI: https://doi.org/10.31579/jnmir/006

Topical Application of Apremilast in the Treatment of Mild to Moderate Psoriasis

  • Srikanth Kalakoti ID 1*
  • and G. Narasimharao Netha ID 2

1 Apramitha Innovations Private Limited, Hyderabad, India.

2 Department of Dermatology, Venereology, Leprology (DVL) Gandhi Medical College and Hospital, Secunderabad, India.

*Corresponding Author: Srikanth Kalakoti, Apramitha Innovations Private Limited, Hyderabad, India.

Citation: Srikanth Kalakoti, G. Narasimharao Netha. Topical Application of Apremilast in the Treatment of Mild to Moderate Psoriasis, J. New Medical Innovations and Research, 2(1): DOI: 10.31579/jnmir/006

Copyright: © 2021 Srikanth Kalakoti. This is an open-access article distributed under the terms of The Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 28 December 2020 | Accepted: 10 February 2021 | Published: 22 February 2021

Keywords: psoriasis; mild to moderate psoriasis; apremilast; topical dosage form; PDE4 inhibitor; topical therapy

Abstract

Background: Psoriasis is a chronic, autoimmune disorder that affects the skin and joints with an approximate global prevalence of 2–3%. Mild to moderate psoriasis is highly prevalent in about 80% of the global psoriatic population (2-3%). Currently available treatment options for mild to moderate psoriasis are topical dosage forms. Though a variety of topical formulations available, they are associated with different side effects.  There is an unmet need for a product that can be used for a prolonged period with minimal side effects.  Hence, Apremilast gel was developed and clinical proof of concept study (POC) was performed to investigate the efficacy and safety in mild to moderate psoriasis patients.

Methods: A single-center randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of apremilast topical gels 2% & 4% w/w, in adult mild to moderate psoriatic patients for 12 weeks. Patients were examined at weeks 0, 2, 4, 8, and 12 weeks to assess the efficacy and safety. At 0 and 8 weeks, blood samples were collected to investigate the pharmacokinetics. The significance in % recovery was calculated statistically.

Results: Both gels exhibited a significant reduction in PASI values when compared with baseline PASI scores. The average percentage inhibition of PASI with test products i.e. 2% and 4% w/w Apremilast topical gels is about 46.8% and 34.6% respectively after 12 weeks of treatment. Both the test products have not shown any adverse effects, hematological & biochemical changes and have exhibited Cmax less than 20ng/ml after 6 hours of application.

Conclusion: Results have shown that topically applied apremilast could be an effective and safe option for the management of mild to moderate psoriasis.

Introduction

Psoriasis is a common, chronic, inflammatory dermatosis seen in practice. The disease is characterized by erythematous, well-demarcated plaques and rounded scales which look like silvery mica [1]. Pruritus may also present in certain cases. Lesions are usually symmetrical and occur on the extensor surfaces such as the elbows knees and on scalp [2]. Psoriasis associated with pruritus results in frequent scratching and contributes substantial psychological, social, and quality of life problems to patients and their families [3]. The current therapy only suppresses the disease symptoms and recurrence is common after stopping the treatment [4, 5]. The disease may undergo spontaneous remission. The treatment of psoriasis depends on the type, the location, and the extent of the lesions [6]. Drugs used in the management of psoriasis include topical emollients, keratolytic agents such as salicylic acid; cytostatic agents such as coal tar, dithranol, glucocorticoids; vitamin D analogs such as calcipotriol; systemic agents etretinate, immunosuppressants such as methotrexate, cyclosporine, mycophenolate; biological agents T cell activation inhibitors such as efalizumab, alefacept; TNF-alpha inhibitors etanercept, infliximab and systemic glucocorticoids [7]. Mild to moderate cases of psoriasis may not warrant any systemic drug therapy, since drugs used in the systemic route can produce toxicity [8]. Topical treatments are commonly prescribed to alleviate psoriasis symptoms, reduce inflammation, and prevent flares. But no new molecules have been approved for the topical treatment of psoriasis in the past few years and treatment guidelines recommend the use of topical corticosteroids, vitamin D analogs, or both.

Corticosteroids are the first-line treatment in the management of psoriasis irrespective of the disease type (mild, moderate or severe) because of their high beneficial levels and are available in a variety of dosage forms including ointment, cream, gel, spray, foam, lotion, etc. But are associated with various side effects such as atrophy, telangiectases, striae, traumatic purpura, perioral dermatitis, hypertrichosis, etc [9].

Vitamin D analogs are another kind of widely accepted topical preparations to manage psoriasis. These manage psoriasis by inhibiting the keratinocyte growth, promote keratinocyte differentiation, and decrease inflammation in psoriatic lesions via vitamin D receptors on keratinocytes and T lymphocytes [10, 11]. Adverse effects such as irritation, hypercalcemia, etc are surfaced with these agents. The studies reported that skin irritation was prominent in sensitive areas such as the face, etc and around 20% of the population reported skin irritation in those sensitive areas [12, 13].

Despite their efficacy, these topical agents are associated with a variety of limitations in their use as a result of application site reactions and safety concerns with long-term use. Hence, novel topical therapies that may potentially improve upon the risk-benefit profile of current treatment options are needed.

Phosphodiesterase 4 (PDE4) is a key regulator of inflammatory cytokine production in psoriasis by blocking the degradation of cyclic adenosine monophosphate [14]. PDE4 activity is increased in circulating inflammatory cells of patients with psoriasis and the inhibition of PDE4 in monocytes in vitro has demonstrated a reduction in the release of pro-inflammatory cytokines [15]. The oral PDE4 inhibitor, apremilast was recently approved for the treatment of psoriatic arthritis and moderate to severe psoriasis [16]. Apremilast inhibits the PDE4 which leads to an increase in the levels of the cyclic adenosine monophosphate, a naturally occurring intracellular secondary messenger that acts as a modulator of inflammatory responses. This leads to the decreasing production of the pro-inflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-23, and interferon-gamma, and increasing production of anti-inflammatory mediators, such as IL-10 [17-19].

Apremilast oral tablets require dose titration to avoid gastrointestinal side effects (nausea and diarrhea) precipitated with the inhibition of PDE4 in non-target tissues [8]. A topical PDE4 inhibitor formulation could address the need for targeted inflammation in skin disease while avoiding undesirable side effects warranted by broad systemic exposure. Hence, an attempt has been made to develop the Apremilast, PDE4 inhibitor, topical gel to treat mild to moderate psoriasis.  The gel will appear white to off-white viscous in nature and consists of different inactive ingredients like carbopol, dimethyl sulfoxide, propylene glycol, glycerin, methyl and propyl parabens, ethanol, etc. A prototype clinical proof of concept study was performed to evaluate the efficacy and safety of apremilast topical gel, 2% and 4% in patients aged more than 18 years with mild to moderate psoriasis.

Although systemic exposure to apremilast upon topical administration may vary with the percentage of body surface area that gets exposed to the medication, the severity of the disease lesions, and skin condition, it was objected to delivering the zero or minimal systemic concentrations.  This novel topical dosage form of apremilast exhibited the drug release to sufficient to elicit pharmacological action and minimized the concentration in the systemic circulation which then helped in minimizing side effects associated with oral apremilast tablets.

Materials and Methods

Study design

The efficacy and safety of Apremilast Topical Gels, 2%, 4% w/w and placebo, in patients with mild to moderate psoriasis were evaluated in a 12-week, Randomized, double-blind, placebo-controlled, three-arm parallel study conducted in 36 volunteers at Gandhi Medical College, Secunderabad, India. The institutional review board approved all study protocols, consent/assent forms, and relevant supporting data. No participant (principal investigator, study staff, participants, parents/guardians, etc) knew the treatment assignment, and blinding was maintained throughout clinical management, data management, and statistical evaluation. The study consisted of a screening visit, a washout period of 14 days, a baseline/randomization visit (0 weeks), and study assessments at weeks 2, 4, 8, and 12. Flow Diagram of the Study is given in figure 1.

Figure 1. Flow chart of the study

Ethical issues

This study was conducted in compliance with the Declaration of Helsinki and the study protocol was reviewed and approved by the Institutional Ethics Committee, Gandhi Medical College & Hospital, Secunderabad, India (DCGI Regd No: ECR/180/Inst/AP/2013/RR-16, Dt.21.06.2017) and the registered no: IEC/GMC/2018/12, Dt. 30.03.2018. The purpose of the study was clearly illustrated to each patient and collected the consent in written from each patient.

Patient’s inclusion and exclusion criteria

A total of 36 patients with mild to moderate psoriasis (Psoriasis Area Severity Index (PASI) < 10) were included in the study. A randomization schedule was prepared using software SAS, Version 9.2, and volunteers are allocated to the individual groups as per the schedule. The inclusion and exclusion criteria of the patients are as follows.

Patient’s inclusion criteria

  1. Diagnosis of mild to moderate plaque psoriasis i.e., PASI score of ≤ 10 for at least 6 months by a dermatologist.
  2. Patients of age ≥ 18 years.
  3. Able to understand and voluntarily give informed consent.
  4. Discontinuation of use of other anti psoriasis agents.
  5. Able to attend all the study visits as per the schedule and other protocol guidelines.

Patient’s exclusion criteria

  1. Suffering from clinically significant diseases other than psoriasis.
  2. Use of phototherapy and those taking systemic medications for psoriasis in the past 28 days.
  3. Any circumstance, including laboratory abnormalities, would keep the subject at undesirable risk if he/she took part in the study.
  4. Prior history of suicide attempt at any time in the subject's lifetime.
  5. Women lactating, pregnant, or planning to become pregnant.
  6. Active substance abuse or a history of substance abuse within 6 months.
  7. Patients participating in any other clinical trials simultaneously.
  8. Patients treated with oral apremilast tablets.

Intervention

Eligible patients gave written consent and underwent treatment with Apremilast/ Placebo topical gel by applying on the affected area twice daily for 12 weeks. Concurrent use of any topical and oral anti psoriasis medications was not allowed during the study.

Apremilast gel treatment

On the day of randomization, the baseline area (psoriasis affected area) was determined by taking the photographs and PASI scores were recorded under the supervision of the principal investigator. Patients were asked to apply a layer of gel on psoriasis affected area twice daily throughout 12 week study period, to apply test drug as needed, and to newly identified psoriatic lesions that appeared after day 1. PI also instructed to subjects to visit bi-weekly or monthly (Week 2, 4, 8 and12) for reviewing the efficacy and safety as per the schedule.

Evaluation

Study assessments i.e. efficacy and safety were performed at weeks 2, 4, 8, and 12 of treatment. The PASI scores were recorded at all visits under the supervision of the principal investigator. Pharmacokinetics of topically administered apremilast was studied by collecting and analyzing the blood samples from the few patients of all three arms on week 0 and week 8. Blood samples collected at 0 hr (pre-dose), 1hr, 1.50 hr, 2 hr, 2.50 hr, 3 hr, 4 hr, and 6hrs after the morning application of the formulation at the investigator’s clinic. The plasma samples are analyzed using a bioanalytical method developed in LC-MS/MS.

Clinical laboratory testings (hematology, biochemistry, and urinalysis) and vital signs were recorded at the time of randomization and after completion of treatment whereas AEs, SAEs, and physical examinations were monitored at all visits during the treatment period. The baseline patients and disease characteristics are presented in Figure 2.

Figure 2: Schematic presentation of Patients' disposition.

Efficacy

The primary efficacy endpoint is to assess the mean percentage change from baseline in PASI at Week 8 and 12. Reduction in PASI scores with 2% and 4% gels by 50%, 75%, and 90% are computed by comparing with baseline PASI score after 12 weeks of treatment. Signs of psoriasis were measured throughout the treatment period on investigator visit days of weeks 2, 4, 8, and 12.

The secondary efficacy endpoints are checking the safety and tolerability of the gels throughout the study period and also measuring the systemic exposure of apremilast in a subset of patients at weeks 0 and 8.

Dermatology Life Quality Index (DLQI) was also considered as one of the measures to assess the efficacy of the developed apremilast topical gels, 2%, 4%, and placebo. DLQI scale was recorded before and after the treatment with the apremilast topical gels and placebo. The results are presented in figure 3.

Figure 3: Variation of severity in deferent visits (week 0 & 8)

Safety

The Primary Safety evaluations included adverse events (AEs), vital signs, X-ray, electrocardiography (ECG), and clinical laboratory parameters including hematological and biochemical limits.

Safety was evaluated by monitoring AEs, clinical laboratory testings (hematology, biochemistry, and urinalysis), vital signs, and physical examinations. Adverse events were categorized based on the severity and relationship to the study drug. Adverse Events that occurred post-treatment (events that occurred after the first dose of medication and up to 14 days post-treatment) were also recorded.  The appearance of newer lesions post-randomization was not captured as AEs but captured separately in CRFs.

Statistical analysis

Statistical analysis of clinical efficacy of apremilast topical gels was carried out with Wilcoxon rank-sum test and the differences were considered as statistically significant when p < 0.05. In order to verify the homogeneity of the three groups, age and baseline disease intensity (baseline PASI scores) between the groups were compared. Baseline PASI scores of 2%, 4%, and placebo groups were compared with PASI scores observed after 12 weeks of treatment. 

The % population achieved PASI 50, 75, and 90 with apremilast topical gel was compared with Phase II and Phase III clinical trials data of apremilast oral tablets intended for moderate to severe psoriasis available in the literature. 

Results

A total of 52 volunteers were scrutinized, 36 of whom were recruited and were randomized into three groups, 2%, 4%, and placebo groups, at a ratio of 12: 12: 12. 16 volunteers did not meet the inclusion criteria and were excluded. 

Of the 12 patients in 2% Apremilast topical gel arm, 10 completed the treatment period of 12 weeks and also responded in the follow-up period (28 days) and 2 did not complete the study. Of the 12 patients in 4% Apremilast topical gel arm, 9 completed the treatment period of 12 weeks and also responded in the follow-up period (28 days) and 3 did not complete the study. Of the 12 patients in the placebo gel arm, 8 completed the treatment period of 12 weeks and also responded in the follow-up period (28 days), 3 did not complete the study and one was withdrawn from the study as he did not respond to the treatment. The patient disposition details are presented in figure 2.

A significant reduction in PASI scores was observed with test products after 12 weeks of treatment when compared with the baseline PASI scores. The mean % recovery with 2% and 4% gels are 46.8% and 34.6% respectively. The percentage of patients who exhibited PASI 50, PASI 75, and PASI 90 with 2% apremilast topical gel are 60.0%, 40.0%, and 10.0% respectively whereas with 4% Apremilast topical gel are 33.3%, 11.1%, and 11.1% respectively. The % recovery with 2% and 4% gels approximately similar and the variation in the PASI with 2% and 4% gels maybe because of variation in the initial PASI scores. The data presented in Figures 4 and 5.

Figure 4: Mean PASI scores (±SD) of 2%, 4%, and Placebo gels at week 0, week 8, and week 12

 

Figure 5: Mean % recovery (±SD) with 2%, 4%, and Placebo gels at week 8 and week 12

Figures 6 and 7 are the pictorial presentations of the percentage recovery before and after treatment. The mean % improvement of DLQI with 2% and 4% gels are 43.1% and 32.9% respectively. The data presented in figure 6.

Figure 6. Mean and % improvement (±SD) of DLQI scores before and after 12 weeks of treatment

During the study period and after completion of treatment, patients were examined for different adverse events, serious adverse events, physical examinations and vital signs.

Figure 7: Variation of severity in different visits (week 0 & 8).

None of the test products including placebo have shown any side effects like irritation, redness, itching or swelling throughout the study period. No hematological and biochemical changes noticed in the subjects after completion of treatment when compared with an initial assessment. No adverse events and serious adverse events (SAEs) were reported with three products (Table 1).

 

Product

Apremilast Topical Gel

Apremilast Tablets

Strength

2%, 4% w/w and Placebo

30mg

Indication

Mild to moderate psoriasis

Moderate to severe psoriasis

Route of administration

Topical

Oral

Treatment period

12 weeks

16 weeks

Dosage form

Topical Gel

Oral tablets

Phase of the study

POC

Phase II

Phase II

Phase III

No of subjects

12

12

12

85

88

562

scores obtained

Actual values*

Literature

Code of the Product

2%

4%

Placebo

Japan

US & Canada

8 different countries including US & Canada

PASI50 (achieving 50)

60.0

33.3

12.5

29.2

35.2

41.7

PASI75 (achieving 75)

40.0

11.1

12.5

21.1

35.2

27.8

PASI90 (achieving90)

10.0

11.1

0

12.9

10.2

9.4

Reported adverse events (%)

Nasopharyngitis

0

0

0

11.8

5.7

7.3

Diarrhoea

0

0

0

9.4

13.6

18.8

Abdominal discomfort

0

0

0

7.1

NR

NR

Psoriasis

0

0

0

4.7

0

NR

Nausea

0

0

0

NR

19.3

15.7

Tension Headache

0

0

0

NR

15.9

5.5

upper respiratory tract infection

0

0

0

NR

15.9

10.2

Reported severe adverse events (%)

SAE (%)

0

0

0

0

4.5

2.1

 NR-Not reported

# data presented in terms of percentages (%)

Table 1: PASI score changes in volunteers used test formulations (Apremilast Topical Gels 2%, 4% and placebo, BID) for 12 weeks from topical route to treat mild to moderate psoriasis.

At weeks 0 and 8 of treatment, blood samples collected from a subset of patients and were analyzed for plasma concentrations of apremilast to assess the systemic exposure levels from both gels (Table 2). An average Cmax of 6.5ng/ml and 3.5 ng/ml on the day of randomization and 4.25 ng/ml and 6.82 ng/ml on week 8 of plasma concentrations of apremilast found with 2% and 4% gels respectively. The absorbed drug from both gels is too less which indicates the maximum amount of drug retaining in the skin layers and eliciting the effect. This could be the reason for zero AEs and SAEs.

Clinical laboratory evaluation was also assessed before and after treatment by the principle investigator. There was no significant change in clinical laboratory parameters in all patients. The mean clinical laboratory results of the subjects who completed 12 weeks of treatment are reported in Tables 2 and 3.

 

S No

Test

Normal Range

Before

After

Range

Average

Range

Average

1

Haemoglobin

13-17 g/dl

11-14

14

10-17

13

2

PCV/HCT

40-50%

33-48

41

32-50

39

3

Total RBC count

4.5-5.5mill/cumm

3.6-5.8

4.8

3.4-6.5

4.6

4

Total WBC count

4000-10000 cells/cumm

5100-12600

8088

4900-25600

8475

5

Platelet count

1.5-4.1 lakhs/cumm

1.6-4.3

2.9

1.6-4.2

2.8

6

Neutrophils

40-80%

42-79

60

46-86

64

7

Lymphocytes

20-40%

16-43

29

8-42

27

8

Eosinophils

1-6%

1-11

3

0-7

2

9

Monocytes

2-10%

4-10

7

2-10

6

10

Basophils

0-2%

0-2

1

0-1

0

Table 2: Summary of Haematology results of all the subjects

S No

Test

Normal Range 

Before

After

Range

Average

Range

Average

1

Total bilirubin

0.3-1.2 mg/dl

0.4-2.7

0.7

0.2-2.3

0.7

2

Direct bilirubin

<0.2 mg/dl

0.1-0.3

0.1

0.1-0.3

0.1

3

Indirect bilirubin

0-0.8 mg/dl

0.3-2.4

0.6

0.1-2.0

0.6

4

ALT (SGPT)

<50 IU/L

9-49

24.7

9.0-76.0

25.6

5

AST (SGOT)

<50 IU/L

16-44

25.3

17-57.0

27.6

6

Alkaline phosphate

30-120 IU/L

56-158

95.4

56-159

98.2

7

Total protein

6.6-8.3 g/dl

6.6-7.5

7.5

6.4-8.4

7.4

8

Albumin

3.4-5 g/dl

3.6-5

4.3

3.7-4.9

4.2

9

Globulin

1.8-3.8 g/dl

2.4-4.2

3.1

2.3-4.1

3.2

10

A/G ratio

0.9-1.8

0.9-2

1.4

1.0-1.9

1.4

11

Random plasma glucose

70-140 mg/dl

76-181.3

99.5

64-239

104.9

12

Serum creatinine

0.67-1.17 mg/dl

0.3-1

0.7

0.4-1.0

0.7

13

Blood urea

17-43 mg/dl

9-36

20.3

Oct-30

18.7

14

Uric acid

3.5-7.2 mg/dl

2.8-8.2

5.2

3.5-7.6

5.3

Table 3: Summary of Biochemistry results of all the subjects

The p values substantiated that there is homogeneity in the age and initial PASI scores between the active gels and placebo gel groups (non-significant variation). This indicates that there is no influence of age and initial PASI scores on % recovery. The statistically significant % recovery was observed, based on p-values, with 2% gel product and no significant recovery observed with 4% gel product placebo gel indicating that test product having clinical efficacy. The p values are reported in Table 4.

S No

Treatments

p-value calculated using Wilcoxon rank-sum test with continuity correction

Remarks

Age

1

2% Vs Placebo

0.0836

Non-significant

2

4% Vs Placebo

0.7027

Non-significant

PASI before Initiating the study

1

2%Vs Placebo

0.130

Non-significant

2

4%Vs Placebo

0.141

Non-significant

Comparison of baseline PASI vs PASI after 12 weeks of treatment (3rd visit PASI vs 7th visit PASI)

1

2%

0.038

Significant

2

4%

0.064

Non-significant

3

Placebo

0.092

Non-significant

Table 4: Significance levels (p values) between the products based Wilcoxon rank-sum test with continuity correction.

Based on the mean % change in PASI, AEs, SAEs, pharmacokinetic data, and on comparing the oral apremilast tablets data, it was concluded that both test products 2% and 4% gels were effective in the treatment of mild to moderate psoriasis.

Discussion

Apremilast topical gel, a novel PDE4 inhibitor, significantly reduced the signs and symptoms of mild to moderate psoriasis in patients.  Its positive efficacy profile was based on 1) decrease in disease severity 2) reduction in psoriasis signs and symptoms; and 3) early and sustained improvement with no side effects. This novel topical dosage form showed improved quality of life by decreasing the psoriasis signs and disruption of itch-scratch cycle.

The significant efficacy of topical apremilast versus placebo was observed in the study. In treating patients with psoriasis, a topical treatment should ideally disturb the inflammatory process and provide protective benefits including improving the skin barrier to reduce antigen access and increasing skin hydration by preventing transdermal water loss. As such topical drug placebos have physiological cutaneous effects, adding to the drug effect in improving the outcome for patients. The incorporation of apremilast into the placebo significantly improved the efficacy in treating psoriasis.

The % recovery (PASI 50, PASI 75, and PASI 90) achieved with topical apremilast gel was compared with % recovery (PASI 50, PASI 75, and PASI 90) achieved with oral apremilast Tablets in Phase II and Phase III clinical trial data. Apremilast tablets, 30 mg (OTEZLA), are indicated for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Although the study duration and indication are slightly different, the data were compared to assess the effectiveness of the topical gel.

Phase II clinical trials oral apremilast tablets carried out in Japan and US&Canada with oral apremilast tablets reported that 29.2 and 35.2% of volunteers have achieved PASI 50. Similarly, phase III clinical trials organized in 8 different countries exhibited that the PASI 50 was achieved by 41.7% of volunteers. While PASI 50 achieved with 2% and 4% apremilast topical gels (60.0% and 33.3%) are comparable with PASI 50 data obtained in clinical trials carried out with oral apremilast tablets.  Although there is variation in the treatment period between topical gel (12 weeks) and oral tablets (16 weeks), the 2% and 4% topical gels have shown as good recovery as that of oral apremilast tablets approximately. The efficacy of both gels (2% and 4% gels) may further increase either on increasing the number of subjects or increasing the treatment period to 16 weeks and it may be higher when compared with oral apremilast tablets.

No adverse events and serious adverse events (SAEs) were reported with three products whereas the oral apremilast tablets reported many AEs and SAEs during 16 weeks of treatment (Table 5).

 

Visit

Week 0 (Visit 3)

Parameter

Tmax (hrs)

Cmax (ng/ml)

AUC (hr*ng/mL)

Formulation

2%

4%

Placebo

2%

4%

Placebo

2%

4%

Placebo

N

8

7

6

8

7

6

8

7

1

Mean

4.8

5.4

0.7

6.5

3.5

0.9

11.5

7.1

0.3

SD

1.7

1

1.6

5.2

2.3

0.2

9.2

5.4

-

Range

2.0-6.0

4.0-6.0

0.0-4.0

1.1-13.9

0.6-7.2

0.0-0.5

2.9-30.0

0.6-15.2

0.3-0.3

Geo.mean

4.5

5.3

-

4.5

2.7

-

8.6

4.9

0.3

Visit

 Week 8 (Visit 6)

N

4

4

7

4

4

7

4

3

2

Mean

4.3

4.5

1.4

4.3

6.8

0.5

14.1

36.1

5.2

SD

2.0

3.0

2.5

1.8

7.7

0.9

9.1

25.4

6.9

Range

2.5-6.0

0.0-6.0

0.0-6.0

1.9-5.8

0.0-17.1

0.00-2.5

5.8-26.9

10.2-60.9

0.4-10.2

Geo.mean

3.9

--

--

3.9

--

--

12.1

28.5

1.9

Table 5: Pharmacokinetic data of Apremilast topical gels and placebo at weeks 0 and 8.

Because of severe adverse side effects and restricted long-term use of topical corticosteroids and topical vitamin D analogs, a safe and effective topical alternate is needed to treat mild to moderate psoriasis. Topical apremilast gel has low systemic absorption reducing the risk of systemic side effects, making it an encouraging treatment alternate to exiting topical therapies. Twice daily application of apremilast gels for 12 weeks demonstrated a favorable safety profile in the study based on (a) low or no incidence of treatment-related adverse events, (b) no serious treatment-related adverse events, (c) low discontinuation rates, (d) no change in hematological or biochemical parameter changes, and (e) no change in vital signs. These efficacy and safety profiles of the novel topical formulation of apremilast gel allow localized therapy at the site of inflammation and reducing the risk of systemic side effects observed with oral apremilast and other PDE4 inhibitors

No adverse events reported with topical apremilast gel including the gastrointestinal adverse events observed with oral apremilast tablets. No subject reported cutaneous AEs such as skin atrophy. Application site irritation is a commonly reported side effect with topical corticosteroids and topical vitamin D analogs. Although a direct comparison study with these agents is not performed, apremilast gel demonstrated a very low incidence of application site irritation or itching. Overall, twice daily application of apremilast topical gel to all areas of the body for 12 weeks treatment demonstrated favorable safety and efficacy profiles.

Topical apremilast gel signifies a first in class non-steroidal topical treatment that inhibits overactive PDE4 in psoriasis to reduce local signs and symptoms that drives exacerbation of the disease. The anti-inflammatory effect on psoriasis pathology is clear, and topical apremilast also provided early and sustained improvement in reducing the red, raised, inflamed patches of skin. The mechanism through which PDE4 regulates red, raised, inflamed patches of the skin is not well understood but is believed to be partially an indirect result of reducing inflammation.

Apremilast topical gel represents a promising new option for patients with mild to moderate psoriasis based on the favorable safety and efficacy profiles. Further, studies need to explore to confirm the potential of topical apremilast gel in patients with impaired renal function.

Conclusions

Apremilast topical gel decreased the disease severity by subsiding the signs and symptoms of psoriasis. The gel product also demonstrated a favorable safety profile in which none of the patients have reported any adverse events. No patients have stopped the medication due to serious adverse effects. Treatment with topical apremilast was well tolerated. In addition, no clinically meaningful differences were observed in the patient’s vital signs, electrocardiograms, and clinical laboratory parameters between treatment groups. Overall, apremilast topical gel targets the principal mechanism of the disease and has the prospective to meritoriously treat mild to moderate psoriasis without the limitations of current treatment options.

Acknowledgements

The authors are indebted to the patients that participated in the study. The authors would like to thanks the support given by the Management and staff of Gandhi Medical College & Hospital, Hyderabad, India.

References

Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.

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Virginia E. Koenig

Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.

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Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.

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Mina Sherif Soliman Georgy

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Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

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Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

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Douglas Miyazaki

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Dr Griffith

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S Munshi

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Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad